US11147763B2 - Vaginal ring with visual indication of use - Google Patents
Vaginal ring with visual indication of use Download PDFInfo
- Publication number
- US11147763B2 US11147763B2 US15/770,722 US201615770722A US11147763B2 US 11147763 B2 US11147763 B2 US 11147763B2 US 201615770722 A US201615770722 A US 201615770722A US 11147763 B2 US11147763 B2 US 11147763B2
- Authority
- US
- United States
- Prior art keywords
- intravaginal ring
- vaginal
- ring
- intravaginal
- indicator
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
- A61K9/0036—Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F6/00—Contraceptive devices; Pessaries; Applicators therefor
- A61F6/06—Contraceptive devices; Pessaries; Applicators therefor for use by females
- A61F6/08—Pessaries, i.e. devices worn in the vagina to support the uterus, remedy a malposition or prevent conception, e.g. combined with devices protecting against contagion
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
- A61M31/002—Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time
Definitions
- the present disclosure relates to polymer-based biomedical devices comprising indicator agents sensitive to the environment of use, methods of using same to enhance adherence to a treatment or usage regimen, and systems for monitoring compliance of use of the polymer-based biomedical device.
- the polymer-based biomedical device may be an intravaginal ring comprised of polymeric material having indicator agent incorporated therein capable of producing a detectable change in response to a stimulus within the vaginal environment.
- Intravaginal rings are a dosage or drug delivery form used to locally or systemically deliver pharmaceutically useful or other bioactive agents into the vagina.
- Such dosage form may be capable of releasing the bioactive agent or agents over an extended period of time, depending on requirements of the agent and the condition treated.
- Intravaginal rings are typically torus-shaped, flexible devices made of biocompatible material, such as silicone, elastomeric material, or thermoplastic material, generally incorporating one or more bioactive agents, such as drugs. Intravaginal rings usually are formulated as matrix or reservoir devices, but other structures may be used.
- Intravaginal rings can offer unique advantages to combat various infections, such as HIV, by delivering drug continuously over the course of an extended period, e.g., a month.
- the simple regimen and low user burden of intravaginal rings may offer protection against HIV infection, for example.
- intravaginal rings do not depend on administering drug before intercourse (e.g., vaginal gels) or performing a daily action (e.g., daily pill).
- ASPIRE The Ring Study
- vaginal rings for pre-exposure prophylaxis (PrEP) delivery critically depends on understanding women's adherence, or the extent women comply with medical instruction.
- adherence of vaginal rings is primarily determined via patient self-report (i.e., questionnaires). This subjective approach is inherently error-prone with the potential for incorrect reports or falsification.
- adherence levels in the ASPIRE and The Ring Study have apparently been challenging at some locations or under some circumstances, as revealed by anecdotal reports.
- women from developing countries often remove their vaginal ring during the month because of opposition from their sexual partner or for other reasons. Before their monthly visit to medical caregivers, the women will reinsert the device.
- the present disclosure relates to intravaginal rings having indicator agent incorporated therein capable of producing a detectable change in response to a stimulus within the vaginal environment.
- the disclosure relates to an intravaginal ring for delivery of bioactive agent to a vaginal environment, the intravaginal ring comprising bioactive agent in a form that is delivered by the intravaginal ring to the vaginal environment when the intravaginal ring is installed in a vaginal locus; and an indicator agent which in interaction of said intravaginal ring with the vaginal environment produces a detectable change indicative of the interaction.
- the disclosure relates to a gynecological health kit, comprising (a) a multiplicity of intravaginal rings, each comprising bioactive agent in a form that is delivered by the intravaginal ring to the vaginal environment when the intravaginal ring is installed in a vaginal locus; and an indicator agent which in interaction of said intravaginal ring with the vaginal environment produces a detectable change indicative of the interaction; and (b) a detector configured to detect the change indicative of the interaction of the intravaginal ring with the vaginal environment.
- the disclosure relates to a method for monitoring compliance with a medical protocol comprising delivery of a bioactive agent to a vaginal environment, said method comprising: installing, or causing to be installed, in a vaginal locus, an intravaginal ring comprising bioactive agent in a form that is delivered by the intravaginal ring to the vaginal environment when the intravaginal ring is installed in a vaginal locus; and an indicator agent which in interaction of said intravaginal ring with the vaginal environment produces a detectable change indicative of the interaction; removing the intravaginal ring form the vaginal locus; and inspecting the intravaginal ring for a detectable change.
- FIG. 1A is a photograph of an aluminum/epoxy mold produced to make intravaginal rings (IVRs) as shown in the photograph of FIG. 1B .
- FIG. 1C is a photograph showing various IVRs which were produced using different color changing formulations.
- FIG. 1D is a photograph of the experimental setup used in the examples.
- FIGS. 2A and 2B illustrate intravaginal ring color change from (i) diffusion of indicators out of the ring ( FIG. 2A ) or (ii) diffusion of biological constituents into the ring ( FIG. 2B ).
- FIG. 3A is a photograph of solutions that previously contained vaginal rings, where the indicator diffused out of the vaginal ring.
- FIG. 3B is a graphical representation of the release of these indicator agents over time.
- FIG. 4 illustrates the results of an evaluation of different pH indicators embedded in silicone as described in the examples.
- FIG. 6 is a graphical representation of the potential for quantification of vaginal rings using RGB values from digital camera images.
- FIG. 7 is a graphical representation of the potential for quantification of vaginal rings using red, green, blue (RGB) values from digital camera images.
- RGB red, green, blue
- FIG. 8A shows the results of post-dip assays to evaluate ring material after exposure to simulated vaginal fluid as described in the examples.
- FIG. 8B shows the assay solutions 48 hours post-assay.
- FIG. 9 shows polyurethane material without indicator (left) and polyurethane containing the bromocresol green indicator.
- FIG. 10 shows EVA material with indicator.
- FIG. 11 shows vaginal rings containing either bromocresol green or bromocresol purple after exposure to either diH 2 O or simulated vaginal fluid.
- FIG. 12A shows biocompatible silicone containing bromocresol purple after immersion in diH 2 O or simulated vaginal fluid for different time periods.
- FIG. 12B shows biocompatible silicone containing bromocresol green after immersion in diH 2 O or simulated vaginal fluid for different time periods.
- biomedical devices e.g., polymer-based bioactive agent delivery devices, comprising indicator agents sensitive to the environment of use.
- biomedical devices may include intravaginal rings, catheters, medical tubing, bandages and the like.
- the present disclosure further relates to intravaginal rings comprised of biocompatible polymeric material having indicator agent incorporated therein capable of producing a detectable change in response to a stimulus within vaginal environments.
- the detectable change may be a visually perceptible color change, such as a color change visible to the human eye, a change determinable by colorimetric or spectrophotometric measurement, or other detectable change.
- Nonlimiting examples of detectable changes in response to a stimulus within vaginal environments include a change in the mechanical properties, the electrical conductivity, the thermal conductivity, the ionic conductivity, the density or the index of refraction of the vaginal ring material.
- the present disclosure is directed to an intravaginal ring for delivery of bioactive agent to a vaginal environment, said intravaginal ring comprising: bioactive agent in a form that is delivered by the intravaginal ring to the vaginal environment when the intravaginal ring is installed in a vaginal locus; and an indicator agent which in interaction of said intravaginal ring with the vaginal environment produces a detectable change indicative of said interaction.
- vaginal ring As used herein, “vaginal ring” (VR) and “intravaginal ring” (IVR) are interchangeable and have the same meaning.
- intravaginal ring design contains solid drug particles dispersed substantially throughout the entire polymeric matrix.
- Such matrix rings typically operate through a permeation mechanism wherein the release rate is dependent on one or more of the solubility of the bioactive agent in the polymer, the ability of the solvated bioactive agent to diffuse through the polymer, the loading of the bioactive agent within the intravaginal ring and the surface area of the intravaginal ring.
- intravaginal ring design is a reservoir configuration wherein the bioactive agent in contained within a reservoir in the ring. Such designs provide constant daily release rates throughout the period of use, substantially conforming to “zero order” release kinetics.
- the intravaginal rings of the disclosure may be either matrix or reservoir rings or other types of intravaginal rings designed for particular purposes such as rings loaded with pods containing bioactive agent or drug cores coated with bioactive agent.
- the range of materials useful for the intravaginal rings of the disclosure may be constrained by the requirements for biocompatibility, flexibility and high bioactive agent permeability.
- the intravaginal rings according to the disclosure will comprise biocompatible materials known for or capable of use in the body.
- the biocompatible material of the vaginal ring preferably will not interfere with delivery of the bio active agent and will not unintentionally degrade during manufacture, transport, and usage.
- the intravaginal rings of the disclosure for use in the body will be comprised of a biocompatible material, e.g., biocompatible polymeric material, such as elastomeric or thermoplastic material.
- the intravaginal rings may comprise a biocompatible material in and/or on which (i) the bioactive agent is present for delivery to the vaginal environment when the intravaginal ring is installed in a vaginal locus, and/or (ii) the indicator agent is present to produce the detectable change during said interaction of said intravaginal ring with the vaginal environment.
- the bioactive agent is in, on, or both in and on the biocompatible material and the indicator agent is in, on, or both in and on the biocompatible material.
- the bioactive agent and the indicator agent may both be comprised in a matrix of the biocompatible material.
- the bioactive agent may be comprised in a matrix of the biocompatible material and the indicator agent may be on a surface of the biocompatible material.
- the bioactive agent is in, on, or both in and on the biocompatible material or the indicator agent is in, on, or both in and on the biocompatible material.
- the bioactive agent may be present in a pod or other defined compartment within the ring and the indicator agent is incorporated in a matrix of the biocompatible material.
- the bioactive agent may be incorporated in a matrix of the biocompatible material and the indicator is present in a defined compartment within the ring.
- Multiple indicator agents may be included within the same ring, in the same or different compartments, such that additional information can be gathered beyond duration of use, including vaginal health, intercourse, and pregnancy. Other combinations are readily understood by those skilled in the art.
- the biocompatible material in aspects of the disclosure, comprises a polymeric material.
- a variety of physiologically acceptable resins or elastomers may be suitable for making vaginal rings, including silicones such as polyorganosiloxanes, e.g., polydimethylsiloxane or a copolymer of dimethylsiloxane and methylvinylsiloxane, conventional silicone rubber, polyurethanes, SILASTIC 382 (Dow Corning), latex rubber, polyamides, polyesters, polytetrafluoroethylene, polyethylene vinyl acetate and nylon.
- silicones such as polyorganosiloxanes, e.g., polydimethylsiloxane or a copolymer of dimethylsiloxane and methylvinylsiloxane
- conventional silicone rubber polyurethanes
- SILASTIC 382 Low Corning
- latex rubber polyamides
- polyesters polytetrafluoroethylene
- the polymeric material comprises polymer selected from the group consisting of silicones, polyorganosiloxanes, polydimethylsiloxane, dimethylsiloxane and methylvinylsiloxane copolymers, silicone rubbers, polyurethanes, latex rubber, polyamides, polyesters, polytetrafluoroethylene, polyethylene vinyl acetate, nylon, and compatible blends, mixtures, and composites of two or more of the foregoing.
- silicones selected from the group consisting of silicones, polyorganosiloxanes, polydimethylsiloxane, dimethylsiloxane and methylvinylsiloxane copolymers, silicone rubbers, polyurethanes, latex rubber, polyamides, polyesters, polytetrafluoroethylene, polyethylene vinyl acetate, nylon, and compatible blends, mixtures, and composites of two or more of the foregoing.
- the intravaginal rings of the disclosure comprise a silicone material (e.g., poly-dimethylsiloxane), polyurethane or ethylene-vinyl-acetate (EVA).
- a silicone material e.g., poly-dimethylsiloxane
- polyurethane e.g., polyurethane
- EVA ethylene-vinyl-acetate
- the intravaginal rings of the present disclosure more preferably contain a silicone material.
- the vaginal rings may comprise a permeable or semi-permeable polymer or polymer surface. Such permeability allows for biological fluids in the vaginal environment to diffuse into the ring. Alternatively, such permeability may allow for an indicator agent to diffuse out of the vaginal ring.
- the biocompatible material thus may be permeable to a bioactive agent for delivery thereof to a vaginal environment when the intravaginal ring is installed in a vaginal locus or, alternatively, be permeable to vaginal fluids comprising fluids in and/or secreted from the vaginal locus, for contact of the vaginal fluids with an indicator agent.
- the stimulus for detectable change, such as color change, in a vaginal environment may include pH, temperature, light, biological elements such as proteins, enzymes, peptides, carbohydrates, lipids, nucleic acids, cellular structures, organelles, bacteria, viruses, yeast, sperm or other biomolecules, redox active elements, metals, ions, moisture, or chemicals associated with biofilms.
- biological elements such as proteins, enzymes, peptides, carbohydrates, lipids, nucleic acids, cellular structures, organelles, bacteria, viruses, yeast, sperm or other biomolecules, redox active elements, metals, ions, moisture, or chemicals associated with biofilms.
- metals may include calcium, magnesium, and the like.
- the stimulus for color change may include conductivity, chelation, surface properties, index of refraction, or mechanical properties of the biocompatible material or indicator agent.
- the indicator agent may be any agent capable of reacting to the environment in which the biomedical device is placed to effect a detectable change.
- a suitable indicator agent in an intravaginal ring in interaction of the intravaginal ring with the vaginal environment, produces a detectable change indicative of the interaction of the intravaginal ring and the vaginal environment.
- the detectable change produced by the indicator agent in interaction of the intravaginal ring with the vaginal environment comprises at least one change selected from the group consisting of color changes, pH changes, temperature changes, conductivity changes, mechanical properties changes, electrical properties changes, optical properties changes, chemical reaction changes, biochemical reaction changes, changes determinable by analytic procedures, changes determinable by assays, and biosensing-detectable changes.
- the detectable change is the result of diffusion of biological components from the vaginal environment into the intravaginal ring. In another aspect of the disclosure, the detectable change is the result of diffusion of the indicator agent out of the intravaginal ring.
- the detectable change is not a change in temperature.
- the detectable change produced by the indicator agent in interaction of the intravaginal ring with the vaginal environment comprises a change in absorbance of incident radiation.
- the change may also comprise a change in absorbance of other types of radiation. Accordingly, in circumstances where a quantitative or definitive demonstration of the change is desired or required, the detectable change may be determined by methods such as colorimetric analysis or absorbance measurements.
- the detectable change produced by the indicator agent in interaction of the intravaginal ring with the vaginal environment comprises a change in a mechanical property of the intravaginal ring.
- the detectable change produced by the indicator agent in interaction of the intravaginal ring with the vaginal environment comprises a visually perceptible color change.
- the indicator agent may be formulated to have a concentration profile that causes the intravaginal ring color to appear different or alter in wavelength as a function of time installed in a vaginal locus and, thus, into the vaginal environment.
- the detectable change produced by the indicator agent in interaction of the intravaginal ring with the vaginal environment is correlative with a length of time in which the intravaginal ring is installed in the vaginal locus.
- the concentration profile of the indicator agent may be formulated to provide temporal information regarding the number of times the intravaginal ring was removed from the vaginal locus.
- concentration profile for example, may signify cycles between low pH and neutral pH or indicate spikes from acidic to basic pH, indicating that intercourse occurred.
- Indicator agents useful for the biomedical devices of the disclosure may be pH-sensitive, chemically-sensitive or environmentally-sensitive, for example.
- indicator agents which effect a visible color change such change may be a function of time and may correspond to any of the stimulus such as pH, temperature, biological elements such as proteins, peptides, bacteria, yeast, sperm or other biomolecules, redox active elements, or chemicals associated with biofilms.
- Indicator agents that respond uniquely to one or more stimuli to generate a visually perceptible response as a function of time advantageously will be incorporated into the intravaginal rings of the disclosure.
- pH-sensitive indicator agents may include bromocresol green, bromocresol purple, bromophenol red, methyl purple, methyl red, azolitmin, bromothymol blue, phenol red, methyl orange, congo red, methyl yellow, thymol blue, malachite green, neutral red, naphtholphthalein, cresol red, thymolphthalein, alizarine yellow R, indigo carmine, cresolphthalein, gentian violet, litmus and the like.
- Chemically-sensitive indicator agents may include redox indicators, pH dependent or pH independent, calcium indicators, sodium indicators, magnesium indicators, and the like.
- Exemplary chemically-sensitive indicator agents may include N-phenylanthranilic acid, nitrophenanthroline, 2,2′-bipyridine, 2,2′ -bipyridine, 5,6-dimethylphenanthroline, o-dianisidine, sodium diphenylamine sulfonate, diphenylbenzidine, diphenylamine, viologen, indigotrisulfonic acid, indigotetrasulfonic acid, indigo carmine, indiomono sulfonic acid, neutral red, methylene blue, thionine, sodium o-cresol indophenol, 2,6-dichlorophenol indophenol, eriochrome black T, calcein EDTA, N-[2-[(acetyloxy)methoxy]-2-oxoethyl]-N-[3-(2-
- the biocompatible intravaginal ring material may contain one or more indicator agents sensitive to the vaginal environment that will change color either upon insertion into the vaginal locus or as a function of time the ring has been installed therein.
- the indicator agent(s) may be mixed within the ring, segmented within the ring or arranged to diffuse out of the ring to effect the detectable change or alteration of wavelength or color.
- a segment of an intravaginal ring may contain one or more indicator agent(s) sensitive to the same or different stimulus.
- a ring may contain multiple segments containing different indicator agents that trigger based on certain particular stimulus, such as ring removal or intercourse.
- the indicator agents advantageously are present in the intravaginal ring in an amount such that upon placement in the vaginal locus, the indicator agent will exhibit a detectable change, such as color change, over an extended period of time, e.g., one to six months.
- a detectable change such as color change
- the ability of the indicator agent to provide a detectable change over a particular period of time will be determined by the intended use of the intravaginal ring and the bioactive agents contained therein.
- the bioactive agent may comprise a time-release form.
- the indicator agent typically will be a biocompatible dye.
- the indicator agent will be a biocompatible dye capable of changing the color of a polymer-based biomedical device based on a stimulus in the environment of use.
- Such dyes include, but are not limited to, sulfonephthalein class of dyes, a rhodamine such as rhodamine-B, fluorescein or a derivative thereof, triphenylmethane dyes such as Brilliant Blue and bromocresol green, bromocresol purple, bromophenol red, and compatible combinations of two or more of the foregoing.
- sulfonephthalein compounds are used.
- a combination of dyes are used that enable color changes over a broad range of pH values.
- the indicator agent is not Alizarin or methyl red.
- biocompatible polymer and indicator agent may include biocompatible silicone material and at least one of rhodamine-B, fluorescein or a derivative thereof, Brilliant Blue, bromocresol green or bromocresol purple.
- Specific combinations may include, by way of example, polydimethyl siloxane (PDMS) and rhodamine-B; PDMS and fluorescein; PDMS and Rhodamine-B/Brilliant Blue; PDMS and Brilliant Blue; PDMS and bromocresol green; and PDMS and bromocresol purple; PDMS and Bromophenol Red; and PDMS and Resazurin.
- the vaginal rings of the present disclosure can be determined by persons skilled in the art using standard techniques.
- the vaginal ring typically has an overall diameter of about 40 mm to about 70 mm, preferably from 54 mm to 60 mm.
- the overall cross-sectional diameter of the ring generally ranges from about 4 mm to about 10 mm, and preferably from about 6 mm to about 9 mm.
- Vaginal rings according to the disclosure may be of any shape or form useful for the intended purpose.
- vaginal rings are torus-shaped, flexible devices. However, other shapes or forms may be used.
- the one or more bioactive ingredients can be any appropriate pharmaceutical, drug or other agent which can be delivered vaginally.
- bioactive agents include steroids, hormones, contraceptives, estrogens, progestins, selective estrogen receptor modulators (SERMs), progesterone receptor modulators (PRMs), anti-virals, anti-retrovirals (including non-nucleoside reverse transcriptase inhibitors (NNRTI)), chemotherapeutic agents such as fluorouracil, anti-fungals, anti-bacterials or anti-protozoals.
- the bioactive agent may be further be selected from the group consisting of anti-fungal, anti-bacterial, antiviral, antiretroviral, anti-inflammatory (steroidal and non-steroidal), antiproliferative, antineoplastic, immunosuppressing, and anesthetic agents, and combinations thereof.
- the bioactive agent comprises at least one agent selected from the group consisting of contraceptive agents, microbicide agents, antiviral agents, and antibacterial agents.
- the bioactive agent may be tenofovir, levonorgestrel (LNG), estrogen, combinations thereof, or the like.
- An intravaginal ring according to the disclosure may contain more than one bioactive agent wherein each bioactive agent is directed to treatment or prophylaxis of a different disease or condition.
- An intravaginal ring according to the disclosure may also contain more than one bioactive agent wherein each bioactive agent is directed to treatment or prophylaxis of the same disease or condition.
- an intravaginal ring according to the disclosure may be used to combat various infections such as sexually-transmitted infections (STI), including, but not limited to HIV or HSV-2, by delivering bioactive agent(s) continuously over the course of an extended period, such as one, two, three or more months.
- STI sexually-transmitted infections
- an intravaginal ring according to the disclosure may be used to prevent various infections such as sexually-transmitted infections (STI), including, but not limited to HIV or HSV-2, and/or prevent pregnancy, by delivering bioactive agent(s) continuously over the course of an extended period, such as one, two, three or more months.
- STI sexually-transmitted infections
- bioactive agent(s) continuously over the course of an extended period, such as one, two, three or more months.
- the intravaginal ring may contain both an estrogen and a progestin, or a progestin alone. Rings of this type are especially suitable for contraception.
- the intravaginal ring may contain a microbicide alone or one or more microbicides in combination. Rings of this type are especially suitable as protection against, or for treating, for example, HIV/AIDS, HSV-2, or other STIs.
- the intravaginal ring may contain both a progestin and a microbicide. Rings of this type are especially suitable for dual purposes in protection against HIV/AIDS, or other STIs, and for contraception.
- the intravaginal ring may use multipurpose prevention technology (MPT) to treat or prevent multiple conditions or diseases.
- MPT multipurpose prevention technology
- “Therapeutically effective amount” as used herein means the amount of bioactive agent needed to obtain the desired therapeutic effect for treatment of a disease or condition in a subject over the time period the intravaginal ring is to be used or installed in the vaginal locus.
- “prophylactically effective amount” refers to the amount of bioactive agent effective to prevent development of disease or condition in the subject over the time period the intravaginal ring is to be used or installed in the vaginal locus.
- the disease is HIV.
- the intravaginal rings according to the disclosure will typically contain a therapeutically effective amount of bioactive agent when treatment of a disease or condition is desired.
- the intravaginal rings according to the disclosure will typically contain a prophylactically effective amount of bioactive agent when prevention of a disease or condition is desired.
- the ring may contain one or more bioactive agents in a therapeutically effective amount, one or more bioactive agents in a prophylactically effective amount, or combinations thereof.
- the intravaginal rings as disclosed herein may be provided in a gynecological health kit.
- a gynecological health kit comprising: (a) a multiplicity of intravaginal rings as described herein; and (b) a detector configured to detect the change indicative of the interaction of the intravaginal ring with the vaginal environment.
- the detector may include a spectrophotometer, mass spectrometer, fluorometer, luminescence spectrometer, infrared spectrometer, pH electrode, oxygen electrode, piezoelectric crystal, density meter, or durometer.
- the detector comprises a digital camera.
- changes in the vaginal ring material resultant from use is detected by the unaided eye.
- Intravaginal rings according to the disclosure may be manufactured by any method known by those skilled-in-the-art, but preferably by injection molding or extrusion, and more preferably by reaction injection molding of silicone material systems.
- injection molding refers to manufacturing processes for producing parts/devices from either thermoplastic or thermosetting materials using suitably designed injection molds.
- the intravaginal rings of the disclosure may be used in methods for determining compliance of a subject with a medical protocol.
- a medical protocol In providing and assessing healthcare interventions, particularly in the developing world, there is a concern about the compliance of a patient with the use of intravaginal rings for therapeutic or prophylaxis treatment.
- the medical personnel need to know if the patient removed the intravaginal ring during the time period the ring was supposed to be providing the treatment or prophylaxis.
- a method for monitoring compliance with a medical protocol comprising delivery of a bioactive agent to a vaginal environment comprising: installing, or causing to be installed, in a vaginal locus, an intravaginal ring of a type as described herein; removing the intravaginal ring form the vaginal locus; and inspecting the intravaginal ring for a detectable change.
- compliance with a treatment regimen involving an intravaginal ring may be determined without reliance on customary subjective assessments, such as interviews. Rather, compliance with instructions and use of an intravaginal ring may be based, for example, on an easy to interpret colorimetric or visual signal change originating from the intravaginal ring. This method enables end users of heath care professions to accurately and rapidly measure the extent of intravaginal ring usage over the time period of the course of treatment or use of the ring.
- the methods of the disclosure enable the quantitative measurement of the detectable change.
- Such quantitative measurement may be by colorimetric analysis, absorption spectroscopy, fluorescence spectroscopy or other measurement methods known in the art. Specific methods include use of a BCA protein assay or Coomassie Blue protein assay; among others.
- the quantitative measurement of detectable change occurs by measuring protein from the vaginal environment deposited on or within the vaginal ring.
- methods for the quantitative measurement of proteins include the Bradford Assay, the NanoOrange® Protein Assay, the EZQTM Protein Assay, or changes in the UV-absorbance.
- the quantitative measurement of detectable change occurs by measuring nucleic acids from the vaginal environment deposited on or within the vaginal ring.
- methods for the quantitative measurement of nucleic acids include intercalating agents such as indole dyes, imidazole dyes, phenanthridine dyes, and acridine dyes.
- the detection of a biomolecule from the vaginal environment on or within the ring is detected using an antibody conjugated to a fluorescent, luminescent, or chromogenic molecule.
- the quantitative measurement of detectable change occurs by measuring a carbohydrate from the vaginal environment deposited on or within the vaginal ring.
- the deposition of glucose on or within the vaginal ring material is detected via fluorescence using horseradish peroxidase and glucose oxidase in the presence of Amplex red reactant.
- polymeric catheters comprising an indicator agent incorporated therein capable of detectable change in response to a stimulus within the environment of use may be used to alert medical practioners of the duration of catheter usage or the possibility of bacterial or other microbes present in the catheter.
- polymeric bandages comprising an indicator agent incorporated therein capable of detectable change in response to a stimulus within the environment of use may be used to assess the requirement to change dressings. The indicator agent is such bandages could provide a color change to indicate the need for a dressing change.
- FIG. 1A A custom machined aluminum/epoxy mold was designed and fabricated to match the dimensions of FDA-approved intra-vaginal ring (“IVR”) devices ( FIG. 1A ). Silicone polymer formulations were cast into the molds and subsequently cured to produce IVRs ( FIG. 1B ). A variety of color changing formulations were evaluated, illustrating the potential to design the IVRs to meet clinical requirements.
- FIG. 1C shows the rings with the formulations including brilliant blue, brilliant blue/rhodamine-B, rhodamine B, fluorescein and no tracer.
- FIG. 1D is a photograph of the experimental setup used to carry out the evaluation.
- FIG. 2A and FIG. 2B Two different approaches were tested to assess the usage of the vaginal ring ( FIG. 2A and FIG. 2B ).
- a system with signal change resultant of indicator diffusion (i) out of the ring was tested ( FIG. 2A ).
- the release profiles showed the ability to release colored tracers with time in simulated vaginal fluids.
- FIG. 5 A custom machined aluminum/epoxy mold with FDA-compatible dimensions as described above was employed to prepare vaginal rings.
- Biocompatible grade (Dow Corning) silicone polymer formulations were cast into the molds and subsequently cured to produce vaginal rings embedded with the bromocresol green tracer ( FIG. 5 )
- the digital camera images of the rings in FIG. 6 were further evaluated using the Red, Green, Blue (RGB) color model using the Image-J open source software.
- RGB Red, Green, Blue
- FIG. 9 shows polyurethane without the bromocresol green (left) and polyurethane containing the bromocresol green indicator (right).
- FIG. 10 shows the ability to incorporate pH indicators into ethylene-vinyl-acetate (EVA).
- FIG. 11 shows VRs that contain either bromocresol green or bromocrescol purple.
- FIG. 12A shows biocompatible silicone containing bromocresol purple.
- FIG. 12B shows biocompatible silicone containing bromocresol green.
Landscapes
- Health & Medical Sciences (AREA)
- Reproductive Health (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Biomedical Technology (AREA)
- Engineering & Computer Science (AREA)
- Gynecology & Obstetrics (AREA)
- Urology & Nephrology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Description
Claims (23)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15/770,722 US11147763B2 (en) | 2015-10-28 | 2016-10-25 | Vaginal ring with visual indication of use |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562247253P | 2015-10-28 | 2015-10-28 | |
US15/770,722 US11147763B2 (en) | 2015-10-28 | 2016-10-25 | Vaginal ring with visual indication of use |
PCT/US2016/058566 WO2017074886A1 (en) | 2015-10-28 | 2016-10-25 | Vaginal ring with visual indication of use |
Publications (2)
Publication Number | Publication Date |
---|---|
US20190070104A1 US20190070104A1 (en) | 2019-03-07 |
US11147763B2 true US11147763B2 (en) | 2021-10-19 |
Family
ID=58630642
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/770,722 Active US11147763B2 (en) | 2015-10-28 | 2016-10-25 | Vaginal ring with visual indication of use |
Country Status (2)
Country | Link |
---|---|
US (1) | US11147763B2 (en) |
WO (1) | WO2017074886A1 (en) |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050250620A1 (en) | 2002-10-09 | 2005-11-10 | Depco, Inc. | Therapeutic color changing putty and method of therapeutic exercise using same |
WO2007103474A2 (en) | 2006-03-07 | 2007-09-13 | University Of Florida Research Foundation, Inc. | Drug adherence monitoring system |
US20120093911A1 (en) * | 2010-10-19 | 2012-04-19 | International Partnership For Microbicides | Platinum-catalyzed intravaginal rings |
US20120259167A1 (en) * | 2011-04-11 | 2012-10-11 | Nancy Karapasha | Single use pessary devices |
US8404272B2 (en) | 2003-06-26 | 2013-03-26 | Poly-Med, Inc. | Fiber-reinforced composite rings for intravaginal controlled drug delivery |
US20130240804A1 (en) | 2012-03-16 | 2013-09-19 | Canopy Valley LLC | Silicone material having a photochromic additive |
US20140129253A1 (en) | 2009-12-23 | 2014-05-08 | Ai Cure Technologies, LLC | Apparatus and Method for Managing Medication Adherence |
US20140209100A1 (en) * | 2011-07-20 | 2014-07-31 | Patrick F. Kiser | Intravaginal devices for drug delivery |
US20150050196A1 (en) * | 2013-08-14 | 2015-02-19 | General Electric Company | Colorimetric indicators for use in medical devices |
-
2016
- 2016-10-25 WO PCT/US2016/058566 patent/WO2017074886A1/en active Application Filing
- 2016-10-25 US US15/770,722 patent/US11147763B2/en active Active
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050250620A1 (en) | 2002-10-09 | 2005-11-10 | Depco, Inc. | Therapeutic color changing putty and method of therapeutic exercise using same |
US8404272B2 (en) | 2003-06-26 | 2013-03-26 | Poly-Med, Inc. | Fiber-reinforced composite rings for intravaginal controlled drug delivery |
WO2007103474A2 (en) | 2006-03-07 | 2007-09-13 | University Of Florida Research Foundation, Inc. | Drug adherence monitoring system |
US20140129253A1 (en) | 2009-12-23 | 2014-05-08 | Ai Cure Technologies, LLC | Apparatus and Method for Managing Medication Adherence |
US20120093911A1 (en) * | 2010-10-19 | 2012-04-19 | International Partnership For Microbicides | Platinum-catalyzed intravaginal rings |
US20120259167A1 (en) * | 2011-04-11 | 2012-10-11 | Nancy Karapasha | Single use pessary devices |
US20140209100A1 (en) * | 2011-07-20 | 2014-07-31 | Patrick F. Kiser | Intravaginal devices for drug delivery |
US20130240804A1 (en) | 2012-03-16 | 2013-09-19 | Canopy Valley LLC | Silicone material having a photochromic additive |
US20150050196A1 (en) * | 2013-08-14 | 2015-02-19 | General Electric Company | Colorimetric indicators for use in medical devices |
Non-Patent Citations (9)
Also Published As
Publication number | Publication date |
---|---|
US20190070104A1 (en) | 2019-03-07 |
WO2017074886A1 (en) | 2017-05-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Moreddu et al. | Laser-inscribed contact lens sensors for the detection of analytes in the tear fluid | |
US7541177B2 (en) | Methods for identifying pathological conditions in a female subject | |
AU2004201228C1 (en) | Compositions Including a Visual Marker and Method of Use Thereof | |
US20060235312A1 (en) | Combination and method including a visual marker for determining compliance with a medication regimen | |
MXPA01010952A (en) | Panty liner with sensor for predicting the start of menstruation. | |
US20050131287A1 (en) | Detection of premature rupture of the amniotic membrane | |
Speer et al. | Novel dissolution method for oral film preparations with modified release properties | |
US5353803A (en) | Apparatus and method for immediate diagnosis of vaginal yeast infections | |
Paghi et al. | Wireless and Flexible Optoelectronic System for In Situ Monitoring of Vaginal pH Using a Bioresorbable Fluorescence Sensor | |
US11147763B2 (en) | Vaginal ring with visual indication of use | |
Murphy et al. | Post-use ring weight and residual drug content as potential objective measures of user adherence to a contraceptive progesterone vaginal ring | |
KR20070098874A (en) | Device and method for identifying and treating vaginal affections | |
US7938776B2 (en) | Examination device for blood detection | |
Anupam et al. | Formulation and evaluation of gastroretentive mucoadhesive films of captopril | |
WO2012176202A1 (en) | Articles and methods for monitoring urinary tract infection | |
Snead et al. | Does tenofovir gel or do other microbicide products affect detection of biomarkers of semen exposure in vitro? | |
Patel et al. | Tenofovir vaginal film as a potential MPT product against HIV-1 and HSV-2 acquisition: formulation development and preclinical assessment in non-human primates | |
Azad et al. | Appraisement of Ranitidine Hydrochloride Tablet (USP150mg) Preparations from Few Selected Companies in Bangladesh | |
Zhao et al. | Physicochemical considerations in the formulation development of silicone elastomer vaginal rings releasing 5-nitroimidazole drugs for the treatment of bacterial vaginosis | |
Johnson et al. | Methods for assessing the adherence to medical devices | |
Machado | Preclinical performance of vaginal semisolid products: technological and safety evaluations assuming physiologic parameters | |
Young | A modular device for vaginal administration of multiple therapeutic agents | |
Zhao | Multipurpose vaginal rings for HIV prevention and treatment of bacterial vaginosis | |
Ayyappan et al. | Formulation development and in-vitro/ex-vivo evaluation of novel buccoadhesive films of metoprolol tartrate using 23 factorial design techniques | |
Chan et al. | Red urine in a returning traveller |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FEPP | Fee payment procedure |
Free format text: ENTITY STATUS SET TO UNDISCOUNTED (ORIGINAL EVENT CODE: BIG.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
AS | Assignment |
Owner name: RESEARCH TRIANGLE INSTITUTE, NORTH CAROLINA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SWARNER, STEPHANIE LYNN;JOHNSON, LEAH MARIE;ROTHROCK, GINGER DENISON;AND OTHERS;SIGNING DATES FROM 20180502 TO 20180711;REEL/FRAME:046591/0784 |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
FEPP | Fee payment procedure |
Free format text: PETITION RELATED TO MAINTENANCE FEES GRANTED (ORIGINAL EVENT CODE: PTGR); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: FINAL REJECTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: RESPONSE AFTER FINAL ACTION FORWARDED TO EXAMINER |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
FEPP | Fee payment procedure |
Free format text: PETITION RELATED TO MAINTENANCE FEES GRANTED (ORIGINAL EVENT CODE: PTGR); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NOTICE OF ALLOWANCE MAILED -- APPLICATION RECEIVED IN OFFICE OF PUBLICATIONS |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: PUBLICATIONS -- ISSUE FEE PAYMENT VERIFIED |
|
STCF | Information on status: patent grant |
Free format text: PATENTED CASE |
|
CC | Certificate of correction |